Abstract for presentation at 11th International Congress of Human Genetics

Genetic Polymorphisms in Xenobiotic Clearance Genes and their Influence on Disease Expression in HNPCC patients

  • Ms Bente Talseth, Discipline of Medical Genetic, Faculty of Health, University of Newcastle, and the Hunter Medical Research Institute, NSW, Australia
  • Dr Cliff Meldrum, Division of Genetics, Hunter Area Pathology Service, John Hunter Hospital, Newcastle, NSW, Australia
  • Dr Janina Suchy, International Hereditary Cancer Center, Department of Genetics and Pathology, Szczecin, Poland
  • Dr Grzegroz Kurzawski, International Hereditary Cancer Center, Department of Genetics and Pathology, Szczecin, Poland
  • Dr Jan Lubinski, International Hereditary Cancer Center, Department of Genetics and Pathology, Szczecin, Poland
  • Prof Rodney Scott, University of Newcastle, Hunter Medical Research Institute,Hunter Area Pathology Service, John Hunter Hospital, Newcastle, NSW, Australia

    • Purpose: Hereditary nonpolyposis colorectal cancer (HNPCC) is associated with germline mutations in DNA mismatch repair genes. There is considerable variation in disease expression that cannot be explained by genotype/phenotype correlation. Disease expression variance is likely to be the result of polymorphic modifier genes. One candidate group of modifiers are the xenobiotic clearance enzyme genes that encode CYP1A1, GSTM1, GSTT1, GSTP1 and NAT2. Alterations in these xenobiotic clearance genes can potentially influence the host response to carcinogen exposure, and thereby alter cancer risk. We have investigated eight polymorphisms in xenobiotic clearance genes to assess the impact on the risk of disease in mutation positive HNPCC patients.
    Methods: DNA samples from 86 Australian and 134 Polish mutation positive HNPCC patients were genotyped for single nucleotide polymorphisms (SNPs) in CYP1A1, GSTM1, GSTT1, GSTP1 and NAT2. The association between the SNPs and disease characteristics; mutation status, disease expression and age of diagnosis of CRC, was tested with Pearson’s Chi-square and Kaplan-Meier survival analysis.
    Results: The Australian HNPCC population displays a significant difference in the genotype frequency distribution between hMLH1 and hMSH2 mutation carriers for SNP NAT2 T341C and NAT2 C481T (conferring to NAT2*5 allele), where hMSH2 mutation carriers have more slow acetylators. This does not affect disease expression or age of diagnosis of CRC in hMSH2 mutation carrier and these findings are unlikely to have a sole effect.
    Conclusion: Evidence from this study is not conclusive, but our data suggests that modifier genes in xenobiotic clearance genes do not influence Australian and Polish HNPCC patients.

    Conference Organiser - ICMS Pty Ltd